Rothmund-Thomson syndrome ((RTS); poikiloderma congenital) is a rare autosomal recessive hereditary disease, the pathophysiology and causative gene of which remain unrevealed. In 1868, a German ophthalmologist, August Rothmund, reported for the first time, 10 patients from an isolated village in Bayern showing crisis of poikiloderma at their youth and exhibiting at a high frequency juvenile cataracts (A. Rothmund, Arch. Ophthalmol. 4:159 (1887)). In 1936, an English ophthalmologist, Sidney Thomson, reported 3 patients with very similar poikiloderma (M. S. Thomson, Br. J. Dermatol. 48:221 (1936)). Two of the three had bone abnormality. Today, these two similar clinical cases are recognized as Rothmund-Thomson syndrome (RTS). Many cases in children of a variety of races affected with this disease have been reported worldwide, and previously over 200 cases of Rothmund-Thomson syndrome had been reported by Vennos et al. (E. M. Vennos et al., J. Am. Acad. Dermatol. 27:750 (1992); E. M. Vennos and W. D. James, Dermatol. Clinics. 13:143 (1995)). Although there is much clinical information on the Rothmund-Thomson syndrome, only clinical background is available for the diagnosis and no method for diagnosis at the laboratory level has been established.
Clinical symptoms of Rothmund-Thomson syndrome include anetoderma and telangiectasia associated with mixed hyperchromic and hypochromic regions during neonatal period, juvenile canities and alopecia prematura, juvenile cataracts, lower stature, congenital skeletal abnormality, and increased risk of mesenchymal tumor. Cytogenetic studies have shown that cells derived from patients with Rothmund-Thomson syndrome are genetically unstable and often exhibit chromosomal recombination, and acquired somatic cell mosaicism can be found in suchcells (K. L. Yingetal., J. Med. Genet. 27:258 (1990); V. M. Der Kaloustian et al., Am. J. Med. Genet. 37:336 (1990); K. H. Orstavik et al., J. Med. Genet. 31:570 (1994); M. Miozzo et al., Int. J. Cancer 77:504 (1998), N. M. Lindor et al., Clin. Genet. 49:124 (1996)). Some of the cytogenetic and clinical findings, including genetic instability in patient cells, juvenile retardation of physical growth, skin abnormality, and high risk of tumorigenesis, are very similar to those findings in Werner syndrome and Bloom syndrome.
Both of the causative genes of Werner syndrome and Bloom syndrome (abbreviated as WRN and BLM, respectively) belong to the RecQ DNA helicase family, and have been identified as homologues of the E. coli RecQ gene, which encodes the DNA helicase (K. Nakayama et al., Mol. Gen. Genet. 200:266 (1985)). In addition to WRN and BLM, SGS1 from budding yeast (S. cerevisiae) and rqh1+ from fission yeast (S. pombe) have been identified as eukaryotic homologues of E. coli RecQ DNA helicase. Mutations in the SGS1 gene are known to result in frequent homologous recombination and non-homologous recombination in budding yeast (S. cerevisiae) cells; likewise, rqh1+ mutations are known to result in frequent recombination in S phase in fission yeast (S. pombe) (S. Gangloff et al., Mol. Cell. Biol. 14:8391 (1994); P. M. Watt et al., Cell 81:253 (1995); E. Stewart et al., EMBO J. 16:2682 (1997)).
Since a trisomy mosaicism of chromosome 8 was found in two of the three Rothmund-Thomson syndrome patients examined (N. M. Lindor et al., Clin. Genet. 49:124 (1996)), the causative gene of Rothmund-Thomson syndrome has been deduced to be located on chromosome 8. However, the causative gene has not yet been identified.